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Intraductal Carcinoma and Prognostic Stage

Group of Prostate, Recent Advances

Jae Y. Ro, M.D., Ph.D.

Houston Methodist Hospital

Weill Medical College of Cornell University,

The University of Texas MD Anderson Cancer Center, Houston, Texas

October 27, 2019 Cornell University

Texas Medical Center

Remember!➢BeST!• Basic

• (effort) Study

• Think

• Enjoy

➢I CARE (integrity, compassion, accountability, respect and excellence)

➢3 Cs (communication, consultation, collaboration)

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1. Basic

• How common prostate cancers?

• Diagnostic approach?

• IDC of prostate and grade group

• WHO Classification of GU

tumors, 4th edition, 2016

• AJCC staging manual, 8th edition

What % of cancers is expected to occur in

GU tract in men in USA in 2019?

• ~10%

• ~20%

• ~30%

• ~50%

• ~70%

What % of cancers occur in GU

tract in men in USA?

• ~10%

• ~20%

* ~30% (32%)

• ~50%

• ~70%• Prostate, 20% (174,650 cases); bladder, 7% (61,700

cases) and kidney, 5% (44,120 cases)

Testis 9,560 cases; penis 2,080 cases

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Ten Leading Cancer Types for the Estimated New Cancer Cases and Deaths By Sex, United States, 2019

CA Cancer J Clin 2019; 69(1):7-34

2. Study

❖Prostate Cancers

• Diagnostic approach

• Intraductal carcinoma

• Grade group

• 8th AJCC staging with prognostic

stage groups

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You have to look for three (3) things!

In any specimens

• Small glands

• Medium/Large glands with architectural

and cytologic atypia

• Stromal abnormalities

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Prostate lesions

Small gland

lesions Large gland

lesions

Stromal

lesions

Basal cells

+ -

Cancer

Mimickers Microacinar

Cancer

Discuss

later

1. Inflammation

2.Stromal tumors,

benign, borderline

and malignant

3.High grade prostate

cancer

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Stromal Lesions

⚫ Inflammation

⚫Poorly diff. adenoca (Gleason pattern 4/5)

⚫Stromal lesions

➢ Stromal hyperplasia

➢ STUMP

➢ Stromal sarcoma

Prostate Carcinoma

Well-diff. and poorly diff. adenocarcinoma

⚫ well-diff. adenocarcinoma

- For screening: three Too’s

(too small, too crowded, and too clear)

- For confirmation: nuclear enlargement,

prominent nucleoli and lack of basal cells

⚫ poorly diff. adenoca

- Uniformity, p. nucleolus, no or low mitoses

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PIN4 cocktail (AMACR, P63, HMCK)

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Erg

Adenocarcinoma

Other helpful features:

• Acid mucin

• crystalloids

• collagenous micronodules (mucinous fibroplasia)

• glomerulation

• Circumferential perineural invasion

• Glands in fat

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Atypical small acinar proliferation (ASAP)

• Size:

1) small number of acini in focus of concern

2) small focus size, average 0.4 mm in greatest dimension

3) lesion breakage at core tip

• Histology:

1) lack of clear histologic detail

2) distortion of acini

3) lack of convincing malignant features

4) clustered growth pattern mimicking benign process such as AAH or atrophy

5) loss of the focus of concern in deeper

6) focal positive HMWCK or negative racemase

7) presence of PIN raising the possibility of tangential cutting

• Inflammation:

1) overdiagnosis of reactive changes or atrophy

2) reactive atypia with nuclear and nucleolar enlargement

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ASAP

• ASAP is a valid diagnostic

category

• Clinical significance: predictive

value for cancer on repeat biopsy

• ASAP predicts cancer : 34% to 60%

• Repeat biopsy and close clinical

follow up

PCA 3 (DD3)• PROGENSA® PCA3 Assay

• mRNA in male urine

• Can reduce unnecessary biopsies

** Not clear whether PCA3 score independently predicts the Gleason score;

not sure whether it can use in active surveillance

High grade prostatic carcinoma

vs. Non-prostatic carcinoma

Prostate Non-prostate

N. monotony + -

Nucleolus prominent variable

Mitoses rare frequent

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Gleason grading

• Gleason grading scheme, original 1977

• Modification, 2005

• Recent, 2015 and 2016 modification

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Gleason ScoringAdenoca

Isolate

gland

Infiltrative:

Pattern 3-5

Fused gl

Incomp gl

Nodular:

Pattern 1 vs. 2

Pattern1 Pattern 2

1)Well defined2)Gl. Size/shape uniform

3) scant stroma

1) Ill defined2) Gl. Size/shape

irregular

3) More stroma

Solid, isolate

cells

Pattern 3 Pattern 4 Pattern 5

Crib/glom glands

No necrosis Necrosis

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Gleason grading, pattern 4

• Fused microacinar glands

• Cribriform glands/Glomeruloid

pattern

• Glands with “poorly formed lumina”

✓Mucinous (colloid) with complex

architecture

✓Ductal-endometrioid with no necrosis

➢No grading for intraductal carcinoma

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Diagnosis of “Poorly Formed Glands” Gleason

Pattern 4 on Needle Biopsy: AJSP2015;39:1331

1. Glands with no or only rare discernible

lumens, 2. Elongated compressed glands and

3. Elongated nests or small cords with no or

rare lumens: “poorly formed” by consensus

and assigned GP4

*** Well-formed but diminutive

• lumens; mixed well-formed

• and diminutive glands, and

• glands with vague lumens

• were not considered “poorly

formed glands”

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Diagnosis of “Poorly Formed Glands” Gleason

Pattern 4 on Needle Biopsy: AJSP2015;39:1331

• Histologic features that are “diagnostic of” GP4:

“poorly formed glands” >10 poorly formed glands

that are not immediately adjacent to other well-

formed glands

• Histologic features that are “against” GP4 “poorly

formed glands: “poorly formed glands” intermixed

with or immediately adjacent to (with < 1 gland

distance from) well-formed glands regardless of their

number

✓ < 5 poorly formed glands regardless of their location

P4

P4

P4

P4

P4

A to C, against pattern 4; D to F, P4

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Gleason 4

Gleason 3

???

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Cribriform glands • In original Gleason grading: small and large

cribriform glands, regular and round, pattern 3:

• In 2005: small cribriform, regular contour and round evenly spaced lumina

• 2014, 2016 grading: all grade 4

• Strong evidence of biochemical recurrence,

extraprostatic extension, positive surgical

margins, distant metastases, and disease-

specific death

• Proposal and vote: 100% agreement

Pattern 3 vs. Pattern 4

Pattern 3 Pattern 4

Gland fusion Discrete gland

units

Fused,

microacinar

gland;

incomplete gland

Cribriform Not allowed Any cribriform

glands/glomerula

-tion with no

necrosis

Other Small but

discrete glands

Hypernephroid:

Not assigned

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Against p5

P5

P5

P5

Pattern 5

• Small cylinders in solid nests

represent Gleason pattern 5.

VOTE: 87% Yes

• Rosette-like spaces in solid medium

to large nests should be

considered to represent Gleason

pattern 5.

VOTE: 88% Yes

Diagnosis of Gleason Pattern 5 on Core

Needle Biopsy: AJSP2015;39:1242

• Diagnostic of GP5 PCa

✓ Large solid tumor nests

✓ Intraluminal coagulative necrosis with or without

karyorrhectic debris

✓ Single cells/cords, 6-10 in a cluster or >10 in a cluster

or intermixed with adjacent well formed glands

✓ Signet ring–like cells in single cells or within nests

• Histologic features “against” GP5 PCa

✓ Small and medium-sized solid tumor nests

✓ Intraluminal amorphous material only

✓ Single cells/cords < 5

✓ Paneth cell–like change in tumor nests

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Variants of Prostate Ca

• Mucinous adenocarcinoma: Gleason pattern 4

may be 3

• Ductal-endometrioid ca: 4 to 5

• Sarcomatoid ca: 5

• Signet ring cell ca: 5

• LELC: 5 and oncocytic ca: 5

• Foamy gland carcinoma: 3, may be higher

• Ca with atrophic & hyperplastic features: 3

• Transition zone ca: 2

• Small cell, TCC, squamous and adenosq ca: not be assigned GG

Intraductal carcinoma

• High grade prostatic intraepithelial

neoplasia

VS.

• Intraductal carcinoma

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Large Cribriform Gland Lesions

Large glands

Cytologic atypia

PIN vs.

Intraductal ca***

No cytologic atypia

CCCH,Central zone

Basal cells

+ _

Ductal/ cribriform Ca

***: > 6 glands, > 1mm, branching contour, dense

cribriform/solid, comedonecrosis, pleomorphism

***Atypical

Cribriform Lesion

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Intraductal carcinoma (IDC-P)

• McNeal & Yemoto, AJSP 1996;20:802

• Guo and Epstein, 2006, Mod Pathol 19:1528

➢ Epithelial cells filling large ducts/acinar with

preservation of basal cells

1) Solid or dense cribriform pattern

2) Loose cribriform or micropapillary with marked

cellular atypia (6 normal or larger) or presence of

comedonecrosis

• Shah et al, 2010, AJSP, 34:470 (ACLs)

➢ > 6 glands with cribriform hyperplastic epithelium

with pleomorphic nuclei, nucleomegaly and

complex architecture (necrosis, solid

architecture, or branching): > 1mm

Intraductal carcinoma (IDC-P)

• Isolated lesion in biopsy: 0.1-0.3%

• With invasive carcinoma: 2.8%

• In radical prostatectomy: 20-40%

• PTEN loss, ERG expression more

common than HG PIN

• Not assigned Gleason grading

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High grade PIN vs. IDCa:Dr. Ro’s modification (Triad)

1. # of glands > 6; > 1mm <6, <1mm

2. Branching contour; Smooth contour

dense cribriform/solid loose cribriform

3. Comedonecrosis; Not present

significant pleomorphism

> 6 times of adjacent nuclei

HGPIN

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IDC-P

IDC-P, solid pattern

IDC-P, micropapillary & necrosis

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Atypical cribriform lesion (ACL). A and B, Two cases with ACLs showing greater

architectural complexity when compared to HGPIN (more than 6 gland

involvement, > 1 mm in size, and branching/irregular contour of glands;×40). Cand D, Each lesion showing micropapillary/loose cribriform patterns, but lacking

nuclear pleomorphism and comedonecrosis (×200). These lesions do not fit witheither HGPINor IDC-P criteria.

Atypical cribriform lesion

• Recent studies have reported that ACL lesions

diagnosed on core needle biopsies were

associated with a substantially increased risk

(55%) of coexistent prostate cancer on

subsequent biopsy and, therefore, require

immediate repeat biopsy.

• 901 radical prostatectomy cases, 22 (2.4%)

cases with ACL in our study.

Atypical cribriform lesions

With cytologic atypia

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• LOH (TP53, RB): 29% in Gleason pattern 4 ca, 60% of IDC-P;

rarely found in HGPIN and Gleason pattern 3 cancers. Prostate.

44:265–70, 2000

• ERG rearrangement: rare in HGPIN, majority seen in IDC-P.

Am J Surg Pathol. 34:478–85, 2010

• Cytoplasmic PTEN loss in 84% of IDC-P, yet very uncommonly

observed in HGPIN. Mod Pathol. 26:587–603, 2013.

• BRCA2 mutation. Eur Urol. 2015;67:496-503

• Molecular studies support the idea that IDC-P is a distinct

lesion from HGPIN and represents a late event in prostate

cancer evolution.

• No genetic markers useful in DX of IDC-P.

IDC-P (Molecular Profiles)

PIN vs IDC-P

• HGPIN is the earliest accepted stage in

carcinogenesis, possessing most of the

phenotypic, biochemical and genetic changes

of cancer without invasion of the basement

membrane of the acini (i.e., precursor lesion

of invasive prostatic adenocarcinoma).

• The pathogenesis of IDC-P remains

controversial. Precursor?

IDC-P• Histologic and molecular evidence strongly

suggests that IDC-P represents late-stage

intraductal spread of existing high-grade

invasive ca, but there are a few reported

cases of pure IDC-P without an associated

invasive ca element.

• In our study, 3 cases with isolated IDC-P

were found, not associated with adjoining

invasive ca component.

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IDC-P

• Rare cases of “precursor-like” IDC-P

have been described in previous studies

• At least a subset of IDC-P may act as

precursor lesion in the HGPIN pathway

of invasive cancer or possibly as a

separate de novo pathway.

Gleason Grading (score):

• Grade (pattern): 1-5, most and second most

common --- most and worst patterns together-

--score

• Score: 2 to 10

• Score 6?

✓Well differentiated?

✓Intermediate (moderately differentiated)?

✓Poorly differentiated?

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Problems with Gleason Score

• Gleason 6 is the lowest biopsy score although the

scale goes from 2-10

• Score 2-5, no longer assigned in biopsies: most

low, score 6, misleading clinicians and patients

• Gleason 7 not homogeneous: 4+3=7 has worse

prognosis than 3+4=7

• Gleason 8-10 is often considered as one group -

high grade disease

Gleason Grade Group

• Grade group 1: Gleason score <6

• Grade group 2: Gleason score 7 (3+4)

• Grade group 3: Gleason score 7 (4+3)

• Grade group 4: Gleason score 8

• Grade group 5: Gleason score 9, 10

Reporting of Gleason Score

Prognostic Grade Groups

• Gleason score ≤ 6:

• Gleason score 3 + 4

• Gleason score 4 + 3

• Gleason score 8

• Gleason score 9-10

• Prognostic Grade Group 1

• Prognostic Grade Group 2

• Prognostic Grade Group 3

• Prognostic Grade Group 4

• Prognostic Grade Group 5

•First reported in BJU Int 2013;111:753-60

•Meta-analysis with >20,000 radical

prostatectomy at 5 institution (Eur Urol

2016;69:428-35)

•.

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BJU Int 2013;115:753-60

• INCORPORTATION

OF PROGNOSTIC

GROUPS

• ENDORSED BY THE

ISUP (2015) & WHO

(2016)

GG1GG2

GG3GG4

GG5

Eur Urol 2016;69-428-35

TNM Stage

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TNM Classification of ProstatePrimary tumor (T)

TX Primary tumor cannot be assessed

T0 No evidence of primary tumor

T1 Clinically inapparent

T2 Organ confined

T3 T3a: EPE, microscopic bladder neck

invasion; T3b: seminal vesicle (s)

T4 Tumor fixed or invade adjacent

structures (ext sphincter, rectum,

bladder, levator muscle, pelvic wall

TNM ClassificationRegional lymph nodes (N)

NX Regional LNs cannot be assessed

N0 No regional LN metastasis

N1 Metastasis to regional node (s)

(Number, size, location of regional LNs involvement)

Distant metastasis (M)

MX no MX in 7th and 8th editions:

M0 No distant metastasis (no pM0, only cM0)

M1 Distant metastasis

M1a Nonregional lymph node (s)

M1b Bone (s)

M1c other sites with or without bone met

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Summary of changes from 7th edition (2010)

• Definition of primary

tumor (T)

• Histologic grade

• AJCC prognostic stage

group

• pT2 only with no substage of

pT2a, b, and c

• Gleason score (2014 criteria)

and Grade group should both

be reported

• Stage III includes select organ-

confined disease tumors based

on PSA and Gleason/Grade

group status

✓PSA > 20, Grade group 5

Level I-IV

AJCC level of evidence, prostate

➢Prostate Cancer

• Level I: PSA, Grade

group/Gleason score

(Integrated in AJCC Prognostic

stage groups)

• Level II: Surgical margin status

• Level III: Histologic types

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AJCC Prognostic Stage Groups

T N M PSA Grade Group Stage group

cT1a-c N0 M0 < 10 1 I

cT2a

pT2 N0 M0 < 10 1 I

cT1-c N0 M0 > 10 < 20 1 IIA

cT2a

cT2b-c N0 M0 < 20 1 IIA

T1-2 N0 M0 < 20 2 IIB

T1-2 N0 M0 < 20 3 or 4 IIC

T1-2 N0 M0 > 20 1-4 IIIA

T3-4 N0 M0 Any 1-4 IIIB

Any T N0 M0 Any 5 IIIC

Any T N1 M0 Any Any IVA

Any T N0 M1 Any Any IVB

Molecular Tests

Molecular Testing: Myriad

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Molecular Testing : Genomic Health

Oncotype DX - Prostate

GPS: Genomic prostate score

Molecular Testing: Decipher

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3. Think!

3. Think

• IDC-P and Grade Groups

• Why important?

• Reflect treatment and prognosis?

• Staging and grading?

• Future targeted therapy?

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4. BeST (Enjoy)

Take Home Messages

• Do your BeST!

1. Basic

2. (effort) Study

3. Think

4. Enjoy

• I CARE/3C practiceOctober 27, 2019

Thank you for

your attention!

October 27, 2018

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